Cellular Immediate-Early Gene Expression Occurs Kinetically Upstream of Epstein-Barr Virus bzlf1 and brlf1 following Cross-Linking of the B Cell Antigen Receptor in the Akata Burkitt Lymphoma Cell Line
Open Access
- 1 December 2010
- journal article
- research article
- Published by American Society for Microbiology in Journal of Virology
- Vol. 84 (23), 12405-12418
- https://doi.org/10.1128/jvi.01415-10
Abstract
The Epstein-Barr virus (EBV) lytic activator genes bzlf1 and brlf1 are conventionally referred to as immediate-early (IE) genes. However, previous studies showed that the earliest expression of these genes was blocked by cycloheximide when the EBV lytic cycle was induced by histone deacetylase (HDAC) inhibitors and protein kinase C agonists. Anti-IgG activates a complex signal transduction pathway that leads to EBV lytic activation in the Akata cell line. Here we demonstrate that in Akata cells, where lytic cycle activation occurs very rapidly after anti-IgG treatment, de novo protein synthesis is also required for induction of bzlf1 and brlf1 expression. New protein synthesis is required up to 1.25 h after application of anti-IgG; bzlf1 and brlf1 mRNAs can be detected 1.5 h after anti-IgG. Five cellular IE genes were shown to be expressed by 1 h after addition of anti-IgG, and their expression preceded that of bzlf1 and brlf1 . These include early growth response genes ( egr1 , egr2 , and egr3 ) and nuclear orphan receptors ( nr4a1 and nr4a3 ). These genes were activated by anti-IgG treatment of Akata cells with and without the EBV genome; therefore, their expression was not dependent on expression of any EBV gene product. EGR1, EGR2, and EGR3 proteins were kinetically upstream of ZEBRA and Rta proteins. Expression of EGR1, ZEBRA, and Rta proteins were inhibited by bisindolylmaleimide X, a selective inhibitor of PKC. The findings suggest a revised model in which the signal transduction cascade activated by cross-linking of the B cell receptor induces expression of cellular IE genes, such as early growth response and nuclear orphan receptor genes, whose products, in turn, regulate bzlf1 and brlf1 expression.Keywords
This publication has 37 references indexed in Scilit:
- Upregulation of STAT3 Marks Burkitt Lymphoma Cells Refractory to Epstein-Barr Virus Lytic Cycle Induction by HDAC InhibitorsJournal of Virology, 2010
- Stimulus Duration and Response Time Independently Influence the Kinetics of Lytic Cycle Reactivation of Epstein-Barr VirusJournal of Virology, 2009
- Activation of the ERK signal transduction pathway by Epstein–Barr virus immediate-early protein RtaJournal of General Virology, 2008
- Histone Hyperacetylation Occurs on Promoters of Lytic Cycle Regulatory Genes in Epstein-Barr Virus-Infected Cell Lines Which Are Refractory to Disruption of Latency by Histone Deacetylase InhibitorsJournal of Virology, 2008
- De Novo Protein Synthesis Is Required for Lytic Cycle Reactivation of Epstein-Barr Virus, but Not Kaposi's Sarcoma-Associated Herpesvirus, in Response to Histone Deacetylase Inhibitors and Protein Kinase C AgonistsJournal of Virology, 2007
- Host shutoff during productive Epstein–Barr virus infection is mediated by BGLF5 and may contribute to immune evasionProceedings of the National Academy of Sciences of the United States of America, 2007
- Epstein-Barr Virus BZLF1 Gene, a Switch from Latency to Lytic Infection, Is Expressed as an Immediate-Early Gene after Primary Infection of B LymphocytesJournal of Virology, 2007
- Induction of the Early Growth Response 1 Gene by Epstein-Barr Virus Lytic Transactivator ZtaJournal of Virology, 2006
- Egr-1 Induces the Expression of Its Corepressor Nab2 by Activation of the Nab2 Promoter Thereby Establishing a Negative Feedback LoopPublished by Elsevier BV ,2005
- Signal transduction by lymphocyte antigen receptorsCell, 1994